Reboxetine for treatment obsessive compulsive disorders and panic disorder

ABSTRACT

This invention relates to the use of reboxetine in the treatment of Obsessive Compulsive Disorders and Panic Disorders.

This application is a 371 of PCT/US99/04288, filed Apr. 2, 1999, whichclaims priority to provisional application No. 60/081,632, filed Apr.13, 1998 and No. 60/085,033, filed May 11, 1998.

FIELD OF THE INVENTION

This invention describes new treatments for several nervous systemdisorders, including: Obsessive Compulsive Disorders, and panicDisorder. The treatment involves the administration of the drugreboxetine.

BACKGROUND

The introduction of tricyclic antidepressants in the early 1960s hasprovided a major advance in the treatment of neuropsychiatric disorders.Reactive and endogenous depressions, diagnoses formerly carrying graveprognostic implications, have become, with the introduction of thetricyclic, manageable disorders with a much smaller toll on the patientand the society as a whole.

The early tricyclic compounds were reuptake inhibitors of all thecatecholamines released in the synaptic cleft, thus resulting inprolongation and enhancement of the dopamine (DA), noradrenaline (NA)and serotonin (5-hydroxytryptamine=5-HT) action. Lack of selectivityalso causes undesired side effects particularly on the acetylcholine(especially the muscarinic component), and histamine mediatedneurotransmission.

Because of these unwanted pharmacodynamic activities, cognitiveimpairment, sedation, urinary and gastrointestinal tract disturbances,increased intraocular pressure were limiting factors in the clinical useof these compounds and often required discontinuation of treatment. Ofutmost concern were also the cardiac toxic effects and the proconvulsantactivity of this group of drugs.

More recently, selective reuptake inhibitors for serotonin (SSRI) havebeen introduced with definite advantages in regard to fewer side effectswithout loss of efficacy.

Here we present the surprising finding that one particular drug from anew category of antidepressants, a so called noradrenaline (NA) reuptakeinhibitor can be used to manage or treat a few special diseases,diseases having symptoms outside of what are usually considereddepression symptoms.

SUMMARY OF THE INVENTION

This patent application describes the treatment of Obsessive CompulsiveDisorders (OCD), and panic Disorder (PD), comprising administering atherapeutically effective, nontoxic dose of reboxetine and derivativesand or pharmaceutically acceptable salts thereof to a patient.

Reboxetine is the generic name of the pharmaceutical substance with thechemical name of 2-(I-((2-ethoxyphenoxy)benzyl)-morpholine and itspharmaceutically acceptable salts. Reboxetine can be a free base, or itcan include reboxetine methanesulfonate (also called reboxetinemesylate) or any other pharmaceutically acceptable salt that does notsignificantly affect the pharmaceutical activity of the substance.

A preferred dose range is 4 to 10 mg per patient per day and the mostpreferred dose is 6 to 8 mg or 8 to 10 mg per patient daily, dependingupon the patient, delivered twice a day (b.i.d.).

ADDITIONAL DESCRIPTION OF THE INVENTION AND DESCRIPTION OF THE PREFERREDEMBODIMENT(S)

Reboxetine is the generic name of the pharmaceutical substance with thechemical name of 2-(I-((2-ethoxyphenoxy)benzyl)-morpholine, and itspharmaceutically acceptable salts. Reboxetine can be a free base, or itcan include reboxetine methanesulfonate (also called reboxetinemesylate) or any other pharmaceutically acceptable salt that does notsignificantly affect the pharmaceutical activity of the substance.Reboxetine and a method of synthesis are described in U.S. Pat. No.4,229,449, issued Oct. 21, 1980, Melloni et. al., incorporated byreference, methods of preparation are described in U.S. Pat. No.5,068,433, issued Nov. 26, 1991, Melloni et. al. and in U.S. Pat. No.5,391,735, issued Feb. 21, 1995, both incorporated by reference.Reboxetine may also be known under the trade name of EDRONAX™.

The pharmaceutical compositions and methods of administration describedin U.S. Pat. No. 4,229,449 at col. 18, lines 33-66 are specificallyincorporated by reference. Twice a day dosing is preferred with currentformulations.

Reboxetine acts as an antidepressant. Antidepressants are frequentlygrouped into categories or “generations”. The first generation ofantidepressants were usually tricyclic antidepressants such asmaprotiline that affected various neurotransmitter systems and areassociated with many undesirable side effects. The second generation ofantidepressants, such as mianserine, mirtrazapine and trazodone arelargely devoid of anticholinergic action and their adrenolytic andantihistaminic effects are weaker. These are contrasted with the thirdgeneration of antidepressants (e.g. SSRI, ipsapirone, viloxazine,reboxetine, bupropione) that mediate only one of the three mainneurotransmitter system for depression (5-HT, noradrenaline, dopamine)and they do not affect muscarine, histamine and adrenergic cerebralsystems. Svestka, J. “Antidepressives of the 3rd, 4th and 5thgeneration,”Cesk-Psychiatr. February 1994; 90(1):3-19. (Czech).

Reboxetine, however, does not act like most antidepressants. Unliketricyclic antidepressants and even selective serotonin reuptakeinhibitors (SSRIs), reboxetine is ineffective in the 8-OH-DPAThypothermia test, indicating that reboxetine is not a selectiveserotonin reuptake inhibitor, instead it is selective for thenoradrenergic system. Thus, reboxetine is not an SSRI, rather it isconsidered a novel, selective, noradrenaline-reuptake inhibitor (NARI).Leonard-BE, “Noradrenaline in basic models of depression.”European-Neuropsychopharmacol. April 1997; 7 Suppl 1: S11-6; discussionS71-3. Unlike most drugs, reboxetine is a highly selectivenorepinephrine uptake inhibitor, with only marginal serotonin and nodopamine uptake inhibitory activity. The compound displays only weak orno anti-cholinergic activity in different animal models and is devoid ofmonoamine oxidase (MAO) inhibitory activity.

Reboxetine is highly potent and fast acting. Our investigations indicatereboxetine has potent antireserpine activity and combines the inhibitoryproperties of classical tricyclic antidepressants on the reuptake ofnoradrenaline with an ability to desensitize ν-adrenergic receptorfunction without showing any appreciable interaction with muscariniccholinergic and I-adrenerigic receptors. Moreover, reboxetine shows lessvagolytic activity than other tricyclic antidepressants.

The inventors have discovered that in addition to its unique properties,mentioned above, reboxetine has been found particularly useful fortreating or enhancing the treatment of a few psychiatric symptoms ordisorders, with greater efficacy and with fewer side effects, than withtreatment by known drugs. Furthermore, the inventors here havediscovered that reboxetine can also be used to treat, or to enhance thetreatment, of a few other specific psychiatric symptoms or disorders.The new symptoms or disorders amenable to treatment with reboxetine areprovided below.

The dosage used to treat all of the disorders described here is asfollows. Reboxetine is well tolerated and has a wide safety range, itcan be administered in a dose range of active ingredient from about 1 toover 20 mg/kg. It is more commonly provided in dosages of from 1 to 20mg per patient per day. The compound may be administered by any suitablemethod including a convenient oral dosage form. A preferred method isoral dosing twice a day. The preferred dose range is 4 to 10 mg perpatient per day and the most preferred dose is 6 to 8 mg or 8 to 10 mgper patient daily, depending upon the patient, delivered twice a day(b.i.d.). It can also be given at dosages of 2, 4, 6, 8, 10 or 12mg/patient per day or fractions thereof: For example, suitableadministrations could be 4 mg in the morning and 2 or 4 mg in theevening. In some patients the ideal dosing would be 3-5 mg in themorning and 3-5 mg in the evening. A skilled practitioner would beexpected to determine the precise level of dosing. The idea dosing wouldbe routinely determined by an evaluation of clinical trials and theneeds of the patient.

The diseases described for treatment here are:

1. Obsessive Compulsive Disorders (OCD)

Obsessive Compulsive Disorder is a condition or state of anxiety thatmay be treated with reboxetine. General descriptions of OCD, may befound in many standard sources, such as, The American Psychiatric PressTextbook of psychiatry, Second Edition, Edited by Robert E. Hales,Stuart C. Yudofsky, and John A. Talbott, copyright 1994, incorporated byreference, especially the chapter on “Anxiety Disorders,” incorporatedby reference. Another of many texts is the Manual of psychiatricTherapeutics, Second Edition, edited by Richard I. Shader, incorporatedby reference, especially Chapter 5, Obsessions and Compulsions, moreparticularly, Section III of that chapter, “OCD” pp. 36 et. seq.,incorporated by reference.

The treatment of Obsessive Compulsive Disorders (OCD) involves theadministration of reboxetine in a manner and form that provide areduction in the symptoms of the disease. See general description abovefor administration of reboxetine. The following study shows thetherapeutic effectiveness of using reboxetine in doses varying from 6 to8 mg to treat OCD. This study is provided to illustrate the usefulnessof using reboxetine as a treatment for OCD and the invention describedherein should not be considered limited by this example.

In a trial involving 10 patients with a DSM-III-R diagnosis of ObsessiveCompulsive Disorder who were all treated with reboxetine for a period of3 to 4 weeks with the dose for the first week at 6 mg (4 mg in a.m. and2 mg in p.m.) with the dose increasing in the second week to 8 mg (4 mgb.i.d.). At CGI last assessment, one patient was judged very muchimproved, 4 were judged much improved, 2 minimally improved, while 3were unchanged. Of the patients who did respond they had a decrease ofthe obsessive-compulsive symptomatology, as measured by the CPRS-OCrating scale, of more than 30 and as much as 73%.

II. Panic Disorder (PD)

panic Disorder is a condition or state of anxiety that may be treatedwith reboxetine. General descriptions of PD, may be found in manystandard sources, such as, The American psychiatric press Textbook ofpsychiatry, Second Edition, Edited by Robert E. Hales, Stuart C.Yudofsky, and John A. Talbott, copyright 1994, incorporated byreference, especially the chapter on “Anxiety Disorders,” incorporatedby reference, another of many texts is the Manual of psychiatricTherapeutics, Second Edition, edited by Richard I. Shader, incorporatedby reference, especially Chapter 25, “Approaches to the Treatment ofAnxiety States,” incorporated by reference.

The treatment of panic Disorder involves the administration ofreboxetine in a manner and form that provide a reduction in the symptomsof the disease. See general description above for administration ofreboxetine.

The following study shows the therapeutic effectiveness of usingreboxetine in doses varying from 6 to 8 mg to treat panic Disorder. Thisstudy is provided to illustrate the usefulness of using reboxetine as atreatment for PD and the invention described herein should not beconsidered limited by this example.

In a trial involving 75 patients that satisfied the DSM-III criteria forthe diagnosis of panic Disorder with or without Agoraphobia (300.01,300.21) and had at least 4 panic attacks in the month preceding theiradmission, in a randomized, placebo controlled parallel group, doubleblind design, 37 on reboxetine and 38 on placebo, the mean number ofmajor panic attacks for patients treated with reboxetine wassignificantly lower than for those on placebo. Phobic symptoms,anticipatory anxiety, occupational functioning, social and familyadjustment were all better at some point in time for those treated withreboxetine than for patients on placebo.

What is claimed is:
 1. A method of treating or enhancing the treatmentof a disorder selected from: a) Obsessive Compulsive Disorders (OCD);and b) Panic Disorder (PD); comprising administering a therapeuticallyeffective, nontoxic dose of reboxetine or any of its derivatives or apharmaceutically acceptable salt thereof to a patient in need thereof.2. The method of claim 1 where reboxetine is used to treat or enhancethe treatment of Obsessive Compulsive Disorders (OCD).
 3. The method ofclaim 1 where reboxetine is used to treat or enhance the treatment ofPanic Disorder (PD).
 4. A method as in any one of claims 1-3 where thereboxetine dose range is from 4 to 10 mg per patient per day.
 5. Amethod as in any one of claims 1-3 where the reboxetine dose range isfrom 6 to 8 mg per patient per day.